Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expre...Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.展开更多
Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necr...Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.展开更多
Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem...Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells(iSCs)are present in the post-stroke mouse(Nakagomi et al.,2009)and human brains(Beppu et al.,2019).展开更多
BACKGROUND Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal dis...BACKGROUND Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal disease on hemodialysis for approximately 20 years,type 2 diabetes mellitus,and atrial fibrillation who presented with two days of epigastric pain.A computed tomography scan of the abdomen revealed intraperitoneal free air and significant intrasplenic gas.Laparoscopy revealed diffuse intestinal gangrene,and acute superior mesenteric ischemia was diagnosed.The patient died within 24 hours owing to profound shock.CONCLUSION Intrasplenic gas is an extremely rare finding on computed tomography imaging in cases of acute mesenteric ischemia.展开更多
Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitatio...Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.展开更多
Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods hav...Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods have been tested to alleviate ischemia-perfusion injury, ranging from using anti-inflammatory drugs, antioxidants, and plants from traditional pharmacopeia to administering RNA interference. However, there is currently no effective therapeutic option available for the treatment of renal IR injury, other than supportive therapies such as renal replacement therapy or hydration. Objective: This present study aimed to evaluate the effect of Guiera senegalensis on renal ischemia reperfusion, a recognized plant for its antioxidant and anti-inflammatory properties. Materials and Methods: Twenty-four (24) adult male Wistar rats were divided into four following groups: SLAM (subjected to a median laparotomy with simulated ischemia);GUIERRA (animals that received 250 mg/kg of guierra senegalensis orally, once a day, for 5 days, with simulated renal ischemia);IR (animals that underwent laparotomy followed by clamping of bilateral renal pedicles for 45 min and followed by reperfusion);GUIERRA + IR (animals given GUIERRA at the dosage of 250 mg/kg per day, for 5 days and then subjected to renal ischemia-reperfusion). Data analysis was performed by ANOVA, and a significance level of p Results: Compared with the I/R group, rats in the GUIERRA + IR group showed reduced histopathological damage scores (p Conclusion: The results of this preliminary work suggest that Guiera senegalensis decreases the degree of tissue damage in renal ischemia-reperfusion cases. This plant seems to be a promising therapeutic;further studies could help to precise the targets of its compounds on ischemia-reperfusion pathways.展开更多
Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug deliv...Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.展开更多
Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
Background:Adolescent depression and school refusal(SR)are prevalent and important global concerns that need to be understood and addressed.Cross-sectional associations have been reported but prospective relationships...Background:Adolescent depression and school refusal(SR)are prevalent and important global concerns that need to be understood and addressed.Cross-sectional associations have been reported but prospective relationships between them remain unclear.This longitudinal study investigated the bidirectional relationships between these two problems among Chinese adolescents.Methods:A longitudinal study was conducted in Taizhou,China,surveying students of three junior high schools,three senior high schools,and one vocational high school.A total of 3882 students completed the questionnaire at baseline(T1);3167 of them completed an identical follow-up questionnaire after 6 months(T2).Depression was assessed via the Patient Health Questionnaire(PHQ-9)and SR via the modified Chinese version of The School Refusal Assessment Scale-Revised(SRAS-R).Cross-lagged panel modeling(CLPM)analysis was conducted to test the reciprocal relationships,adjusting for socio-demographic factors.Multiple group analysis was conducted to test whether the CLPM differed by gender and grade.Results:Statistically significant bidirectional relationships were found.A higher level of SR assessed at T1 is prospectively associated with a higher level of depression at T2(β=0.07,p=0.006);a higher level of depression at T1 also is prospectively associated with a higher level of SR at T2(β=0.14,p<0.001).Such models differed significantly by neither gender nor grade.Conclusion:SR and depression should be seen as each other’s mutually reinforcing association.The bidirectional relationships potentially result in a vicious cycle.Early interventions may target both problems concurrently.Future studies may involve more time points and test some mediators.展开更多
Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake ...Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake eyes”sign.We discuss how these signs,while visually apt,convey no pathophysiologic context and propose renaming this finding the“snake bite sign”.The image still evokes two punctate marks,yet the metaphor extends to a snake bite(two fang-like dots)rather than two bright foci(eyes)staring back at the viewer.Moreover,besides the sign metaphorically resembling a traumatic puncture of the two fangs,on the occasion of a venomous snake bite occurring elsewhere,additional neurological consequences may occur,paralleling the neurological deficits seen in anterior spinal artery infarction and several mimicking myelopathies,thus further high-lighting the analogy.Such clinically driven terminology may facilitate teaching,enable diagnostic recall,and improve interdisciplinary communication.展开更多
Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease in...Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.展开更多
BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and proced...BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and procedural outcomes in PEVI.METHODS A prospective observational study was performed in 186 consecutive patients(65±12 years)at an academic medical center from January 2019 to April 2020(mean follow-up of 3.9±3.6 months)comparing the gender radiation disparity and outcomes of PEVI(n=147 underwent intervention,79.0%).Groups were divided into women(n=99,53.2%)and men(n=87,48.4%).Primary endpoints included air kerma,dose area product(DAP),fluoroscopy time,and contrast use.Secondary endpoints included all-cause mortality,acute myocardial infarction,acute kidney injury,stroke,repeat revascularization,major adverse limb event,and the composite of complications.RESULTS Men showed increased DAP compared with women(15221.2±25858.5µGy×m^(2) vs 9251.7±9555.3µGy×m^(2),P=0.047),but no significant difference in air kerma or any other primary endpoints.In the secondary endpoints,no significant diffe-rence was found between gender.CONCLUSION Men had increased DAP indicating more radiation absorption in the exposed area.Gender outcomes showed no difference in complications.Thus,PEVI can be safely performed in men or women.展开更多
[Objectives]To investigate the protective effects and underlying mechanisms of agarwood essential oil against isoprenaline(ISO)-induced myocardial ischemia(MI)in mice.[Methods]Utilizing network pharmacology methods,th...[Objectives]To investigate the protective effects and underlying mechanisms of agarwood essential oil against isoprenaline(ISO)-induced myocardial ischemia(MI)in mice.[Methods]Utilizing network pharmacology methods,the active components,targets,and MI-related targets of agarwood were identified.Subsequently,Gene Ontology(GO)functional analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed on the identified targets.The efficacy and predictive pathways were evaluated using MI mice.Thirty male C57 mice were randomly divided to five groups:the control group(CTL),the model group(MOD),the positive control group(Pro),the low-dose agarwood essential oil group(Y01-L),and the high-dose agarwood essential oil group(Y01-H).Mice in each treatment group received continuous intragastric administration for 14 d.Beginning on day 8,1 h post administration,mice in all groups except the control group were intraperitoneally injected with ISO at a dose of 10 mL/kg daily for 7 d.The control group received an equivalent volume of normal saline via intraperitoneal injection during this period.One hour following the final administration,blood samples were collected under anesthesia,and the heart was excised and weighed to determine the organ index.The activities of lactate dehydrogenase(LDH)and superoxide dismutase(SOD),and the content of malondialdehyde(MDA)in mouse serum were measured using biochemical assay kits.The protein expression levels of HIF-1α,P-AKT,and P-PI3K were analyzed using Western blot assay.[Results]The results of the network pharmacology analysis identified AKT1,MAPK14,and other targets as common to both agarwood and MI.GO functional analysis and KEGG pathway enrichment analysis demonstrated a significant association with the HIF-1αsignaling pathway.The validation results in mice demonstrated that the active component,agarwood essential oil Y01,effectively inhibited cardiac swelling induced by ischemia.Serological indicators revealed that,compared to the model group,Y01 dose-dependently decreased serum MDA level and LDH activity(P<0.001)while increasing SOD activity(P<0.01,P<0.001).The Western blot assay demonstrated that Y01 significantly upregulated the protein expression levels of HIF-1α,P-AKT,and P-PI3K.[Conclusions]Y01 has the potential to mitigate myocardial injury induced by ischemia through the modulation of the HIF-1αand AKT/PI3K signaling pathways,thereby enhancing cardiac function.展开更多
The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current st...The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.展开更多
Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of...Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of AEF in the CA1 and CA3 areas of the hippocampus over time following cerebral ischemia-reperfusion(IR)injury have not been well elucidated.Objectives:We investigated chronological changes in AEF in the gerbil hippocampal CA1 area from 3 h to 10 days following transient forebrain ischemia(TFI),and examined their association with neuronal death and tissue repair following IR injury.Changes in the CA3 area were also examined at 10 days post-TFI for comparative purposes.Methods:Neuronal death was confirmed using histochemistry,immunohistochemistry,and histofluorescence.Changes in AEF were examined by double immunofluorescence with glial fibrillary acidic protein(GFAP)and glucose transporter 1(GLUT1),and by transmission electron microscopy(TEM)for ultrastructural changes.Results:Significant TFI-induced neuronal death occurred in the CA1 area on day 5 following IR injury and persisted until 10 days after TFI,while no neuronal death(or loss)was found in the CA3 area after TFI.Looking at TFI-induced changes in AEF,at 3 and 6 h after TFI,GFAP-immunoreactive(+)AEF in the CA1 area appeared swollen and harbored enlarged,dark mitochondria,and the swelling was reduced by 1-day post-TFI.On 2 and 5 days following TFI,GFAP+AEF were markedly enlarged and fragmented,containing shrunken mitochondria,vacuolations,and sparse organelles.Ten days post-TFI,the ends of GFAP+astrocytic processes extended to microvessels,appeared edematous,and were filled with cellular debris.In the CA3 area,AEF was slightly dilated at 10 days after TFI.These findings indicate that damage to or disruption of AEF in the CA1 area occurs in the early phase after 5-min TFI but is rarely observed in the CA3 area.Conclusion:Taken together,damage to or disruption of AEF following ischemic insults may be strongly linked to neuronal death/loss.展开更多
Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effec...Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effects of 20-hydroxyecdysone(20E)on hindlimb skeletal tissue following tourniquet-induced ischemia/reperfusion injury.Methods:Animals were divided into 4 groups—control group(Control),Control+20E(C+20E),mice with IRI(IRI),and mice with IRI+20E(IRI+20E).IRI was modeled by applying a tourniquet to the hind limb for 2 h with reperfusion for 1 h.5 mg/kg of 20E was administered intraperitoneally for 14 days.Afterward,the physical activity of mice,the histological structure of the quadriceps femoris,the expression of genes encoding proteins induced by hypoxia and involved in tissue adaptation to ischemia,and the functional parameters of skeletal muscle mitochondria were assessed.Results:It was shown that IRI of the limbs leads to functional disorders,depression of muscle function,accumulation of malondialdehyde(MDA)in mitochondria,and a decrease in their Ca2+buffering capacity,as well as an increase in the expression of HIF-1α,VGEF-A,PGC1αand PDGF-BB genes associated with adaptation to ischemia.20E reduced the intensity of degenerative processes in skeletal muscles,which was expressed in a decrease in the number of centrally nucleated fibers.Analysis of gene expression levels indicated a high degree of adaptation of animals to IRI.20E reduced the level of MDA in mitochondria,but did not affect the rate of respiration and calcium retention capacity of organelles both in normal conditions and during IRI.Conclusion:20E partially alleviates the skeletal muscle damage caused by IRI and can be used as part of combination therapy.展开更多
BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mech...BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mechanism remains unclear.Circular RNAs(circRNAs),which are formed from protein-coding genes,can sequester microRNAs or proteins,modulate transcription and interfere with splicing.Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury.AIM To explore the role and mechanism of circRNAs in myocardial I/R injury.METHODS We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery,and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining.Then,left ventricular samples from different groups were selected for mRNA-sequence,and differential gene screening was performed on the obtained results.The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment analysis were performed,respectively.Then,the obtained circRNA and microRNA(miRNA)were paired for analysis,and the binding sites of miRNA and mRNA were virtual screened.Finally,the obtained circRNA,miRNA and mRNA were constructed by ceRNA mutual most useful network.RESULTS We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group.A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed(fold change≥2,P<0.05).GO and KEGG functional analyses of these circRNAs were performed.GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes.KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis.Furthermore,a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed,revealing that mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 might be key regulators of myocardial I/R injury.CONCLUSION This research provides new insights into the mechanism of myocardial I/R,which mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.展开更多
Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats wer...Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats were divided into the Control,Model,AMI positive control(Propranolol hydrochloride,30 mg/kg),low dose TFSB(50 mg/kg),and high dose TFSB(100 mg/kg)groups.Rats received the corresponding treatment by intragastric administration once daily for 10 consecutive days.Electrocardiogram,myocardial enzyme,triphenyltetrazolium chloride staining,hematoxylin-eosin,and enzyme-linked immunosorbent assay were performed to evaluate the protective effect of TFSB on AMI rats.Then,the UHPLC-Q-Orbitrap MS method based on serum metabolomics was utilised to search for metabolic biomarkers and metabolic pathways.Subsequently,Western blot and RT-PCR techniques were employed to identify the respective genes and proteins.Results:Pharmacodynamics revealed that TFSB could ameliorate AMI in rats.The results of the metabolomics analysis indicated that the alterations in metabolic profile observed in rats with AMI were partially improved by treatment with TFSB.Moreover,the mRNA expression levels of 5-lipoxygenase(5-LOX)and 15-lipoxygenase(15-LOX)and the protein expression levels of 5-LOX,15-LOX,interleukin-1β(IL-1β),and NF-κB p65 were reduced following treatment with TFSB.Conclusion:The potential treatment of TFSB in AMI may be ascribed to its ability to regulate arachidonic acid metabolism.展开更多
Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unre...Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols(PPAPs),named hyperhomanoons A-E(1-5),and one known analog,hypersampsone O(6),were isolated from Hypericum patulum.Among these,compound 6 demonstrated potent protective effects against CoCl_(2)-induced hypoxic injury in hepatocytes.Furthermore,in a murine model of hepatic IRI induced by vascular occlusion,pretreatment with 6 markedly alleviated liver damage and reduced hepatocyte apoptosis.This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI,underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
文摘Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.
基金Shanghai Rehabilitation Medical Association,Grant/Award Number:2023JGKT24China Rehabilitation Medical Association,Grant/Award Number:KFKT-2023Shanghai“14th Five-Year Plan”Traditional Chinese Medicine Specialty and Traditional Chinese Medicine Emergency Capacity Improvement Project,Grant/Award Number:ZYTSZK2-7。
文摘Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.
基金partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15K0672318K07380)the Japan Agency for Medical Research and Development (AMED) (21nk0101538h0002) (to TN)。
文摘Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells(iSCs)are present in the post-stroke mouse(Nakagomi et al.,2009)and human brains(Beppu et al.,2019).
文摘BACKGROUND Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal disease on hemodialysis for approximately 20 years,type 2 diabetes mellitus,and atrial fibrillation who presented with two days of epigastric pain.A computed tomography scan of the abdomen revealed intraperitoneal free air and significant intrasplenic gas.Laparoscopy revealed diffuse intestinal gangrene,and acute superior mesenteric ischemia was diagnosed.The patient died within 24 hours owing to profound shock.CONCLUSION Intrasplenic gas is an extremely rare finding on computed tomography imaging in cases of acute mesenteric ischemia.
基金supported by STI2030-Major Projects,No.2022ZD0207600(to LZ)the National Natural Science Foundation of China,Nos.32070955(to LZ),U22A20301(to KFS)+3 种基金the Natural Science Foundation of Guangdong Province,No.2021A1515012197(to HO)Guangzhou Core Medical Disciplines Project,No.2021-2023(to HO)Key Research and Development Plan of Ningxia Hui Automomous Region,No.2022BEG01004(to KFS)Science and Technology Program of Guangzhou,China,No.202007030012(to KFS and LZ)。
文摘Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.
文摘Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods have been tested to alleviate ischemia-perfusion injury, ranging from using anti-inflammatory drugs, antioxidants, and plants from traditional pharmacopeia to administering RNA interference. However, there is currently no effective therapeutic option available for the treatment of renal IR injury, other than supportive therapies such as renal replacement therapy or hydration. Objective: This present study aimed to evaluate the effect of Guiera senegalensis on renal ischemia reperfusion, a recognized plant for its antioxidant and anti-inflammatory properties. Materials and Methods: Twenty-four (24) adult male Wistar rats were divided into four following groups: SLAM (subjected to a median laparotomy with simulated ischemia);GUIERRA (animals that received 250 mg/kg of guierra senegalensis orally, once a day, for 5 days, with simulated renal ischemia);IR (animals that underwent laparotomy followed by clamping of bilateral renal pedicles for 45 min and followed by reperfusion);GUIERRA + IR (animals given GUIERRA at the dosage of 250 mg/kg per day, for 5 days and then subjected to renal ischemia-reperfusion). Data analysis was performed by ANOVA, and a significance level of p Results: Compared with the I/R group, rats in the GUIERRA + IR group showed reduced histopathological damage scores (p Conclusion: The results of this preliminary work suggest that Guiera senegalensis decreases the degree of tissue damage in renal ischemia-reperfusion cases. This plant seems to be a promising therapeutic;further studies could help to precise the targets of its compounds on ischemia-reperfusion pathways.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2023MC168the National Natural Science Foundation of China,No.31670989the Key R&D Program of Shandong Province,No.2019GSF107037(all to CS).
文摘Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
基金funded by Science and Technology Program of Wenzhou(Y20220843).
文摘Background:Adolescent depression and school refusal(SR)are prevalent and important global concerns that need to be understood and addressed.Cross-sectional associations have been reported but prospective relationships between them remain unclear.This longitudinal study investigated the bidirectional relationships between these two problems among Chinese adolescents.Methods:A longitudinal study was conducted in Taizhou,China,surveying students of three junior high schools,three senior high schools,and one vocational high school.A total of 3882 students completed the questionnaire at baseline(T1);3167 of them completed an identical follow-up questionnaire after 6 months(T2).Depression was assessed via the Patient Health Questionnaire(PHQ-9)and SR via the modified Chinese version of The School Refusal Assessment Scale-Revised(SRAS-R).Cross-lagged panel modeling(CLPM)analysis was conducted to test the reciprocal relationships,adjusting for socio-demographic factors.Multiple group analysis was conducted to test whether the CLPM differed by gender and grade.Results:Statistically significant bidirectional relationships were found.A higher level of SR assessed at T1 is prospectively associated with a higher level of depression at T2(β=0.07,p=0.006);a higher level of depression at T1 also is prospectively associated with a higher level of SR at T2(β=0.14,p<0.001).Such models differed significantly by neither gender nor grade.Conclusion:SR and depression should be seen as each other’s mutually reinforcing association.The bidirectional relationships potentially result in a vicious cycle.Early interventions may target both problems concurrently.Future studies may involve more time points and test some mediators.
文摘Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake eyes”sign.We discuss how these signs,while visually apt,convey no pathophysiologic context and propose renaming this finding the“snake bite sign”.The image still evokes two punctate marks,yet the metaphor extends to a snake bite(two fang-like dots)rather than two bright foci(eyes)staring back at the viewer.Moreover,besides the sign metaphorically resembling a traumatic puncture of the two fangs,on the occasion of a venomous snake bite occurring elsewhere,additional neurological consequences may occur,paralleling the neurological deficits seen in anterior spinal artery infarction and several mimicking myelopathies,thus further high-lighting the analogy.Such clinically driven terminology may facilitate teaching,enable diagnostic recall,and improve interdisciplinary communication.
基金supported by grants from the National Natural Science Foundation of China(U21A20400,81973789,82004327).
文摘Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.
文摘BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and procedural outcomes in PEVI.METHODS A prospective observational study was performed in 186 consecutive patients(65±12 years)at an academic medical center from January 2019 to April 2020(mean follow-up of 3.9±3.6 months)comparing the gender radiation disparity and outcomes of PEVI(n=147 underwent intervention,79.0%).Groups were divided into women(n=99,53.2%)and men(n=87,48.4%).Primary endpoints included air kerma,dose area product(DAP),fluoroscopy time,and contrast use.Secondary endpoints included all-cause mortality,acute myocardial infarction,acute kidney injury,stroke,repeat revascularization,major adverse limb event,and the composite of complications.RESULTS Men showed increased DAP compared with women(15221.2±25858.5µGy×m^(2) vs 9251.7±9555.3µGy×m^(2),P=0.047),but no significant difference in air kerma or any other primary endpoints.In the secondary endpoints,no significant diffe-rence was found between gender.CONCLUSION Men had increased DAP indicating more radiation absorption in the exposed area.Gender outcomes showed no difference in complications.Thus,PEVI can be safely performed in men or women.
基金Supported by Science and Technology Project of Zhongshan City(2022B1125,2021B2046)Medical Scientific Research Projects of Zhongshan City(2023A020355)+1 种基金Scientific Research Projects of the Traditional Chinese Medicine Bureau of Guangdong Province(20251431)University-Hospital Joint Fund Project of Guangzhou University of Chinese Medicine(GZYZS2024D08).
文摘[Objectives]To investigate the protective effects and underlying mechanisms of agarwood essential oil against isoprenaline(ISO)-induced myocardial ischemia(MI)in mice.[Methods]Utilizing network pharmacology methods,the active components,targets,and MI-related targets of agarwood were identified.Subsequently,Gene Ontology(GO)functional analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed on the identified targets.The efficacy and predictive pathways were evaluated using MI mice.Thirty male C57 mice were randomly divided to five groups:the control group(CTL),the model group(MOD),the positive control group(Pro),the low-dose agarwood essential oil group(Y01-L),and the high-dose agarwood essential oil group(Y01-H).Mice in each treatment group received continuous intragastric administration for 14 d.Beginning on day 8,1 h post administration,mice in all groups except the control group were intraperitoneally injected with ISO at a dose of 10 mL/kg daily for 7 d.The control group received an equivalent volume of normal saline via intraperitoneal injection during this period.One hour following the final administration,blood samples were collected under anesthesia,and the heart was excised and weighed to determine the organ index.The activities of lactate dehydrogenase(LDH)and superoxide dismutase(SOD),and the content of malondialdehyde(MDA)in mouse serum were measured using biochemical assay kits.The protein expression levels of HIF-1α,P-AKT,and P-PI3K were analyzed using Western blot assay.[Results]The results of the network pharmacology analysis identified AKT1,MAPK14,and other targets as common to both agarwood and MI.GO functional analysis and KEGG pathway enrichment analysis demonstrated a significant association with the HIF-1αsignaling pathway.The validation results in mice demonstrated that the active component,agarwood essential oil Y01,effectively inhibited cardiac swelling induced by ischemia.Serological indicators revealed that,compared to the model group,Y01 dose-dependently decreased serum MDA level and LDH activity(P<0.001)while increasing SOD activity(P<0.01,P<0.001).The Western blot assay demonstrated that Y01 significantly upregulated the protein expression levels of HIF-1α,P-AKT,and P-PI3K.[Conclusions]Y01 has the potential to mitigate myocardial injury induced by ischemia through the modulation of the HIF-1αand AKT/PI3K signaling pathways,thereby enhancing cardiac function.
基金supported by the National Natural Science Foundation of China(Grant Nos.82030012,81670263,82170444,82270476,82270361,and 82100433)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.24KJA310003)。
文摘The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
基金supported by 2024 Research Grant from Kangwon National University(M.C.S)and the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2021R1A2C1094224)(J.H.A).
文摘Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of AEF in the CA1 and CA3 areas of the hippocampus over time following cerebral ischemia-reperfusion(IR)injury have not been well elucidated.Objectives:We investigated chronological changes in AEF in the gerbil hippocampal CA1 area from 3 h to 10 days following transient forebrain ischemia(TFI),and examined their association with neuronal death and tissue repair following IR injury.Changes in the CA3 area were also examined at 10 days post-TFI for comparative purposes.Methods:Neuronal death was confirmed using histochemistry,immunohistochemistry,and histofluorescence.Changes in AEF were examined by double immunofluorescence with glial fibrillary acidic protein(GFAP)and glucose transporter 1(GLUT1),and by transmission electron microscopy(TEM)for ultrastructural changes.Results:Significant TFI-induced neuronal death occurred in the CA1 area on day 5 following IR injury and persisted until 10 days after TFI,while no neuronal death(or loss)was found in the CA3 area after TFI.Looking at TFI-induced changes in AEF,at 3 and 6 h after TFI,GFAP-immunoreactive(+)AEF in the CA1 area appeared swollen and harbored enlarged,dark mitochondria,and the swelling was reduced by 1-day post-TFI.On 2 and 5 days following TFI,GFAP+AEF were markedly enlarged and fragmented,containing shrunken mitochondria,vacuolations,and sparse organelles.Ten days post-TFI,the ends of GFAP+astrocytic processes extended to microvessels,appeared edematous,and were filled with cellular debris.In the CA3 area,AEF was slightly dilated at 10 days after TFI.These findings indicate that damage to or disruption of AEF in the CA1 area occurs in the early phase after 5-min TFI but is rarely observed in the CA3 area.Conclusion:Taken together,damage to or disruption of AEF following ischemic insults may be strongly linked to neuronal death/loss.
基金supported by a grant from the Russian Science Foundation(23-75-01061)。
文摘Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effects of 20-hydroxyecdysone(20E)on hindlimb skeletal tissue following tourniquet-induced ischemia/reperfusion injury.Methods:Animals were divided into 4 groups—control group(Control),Control+20E(C+20E),mice with IRI(IRI),and mice with IRI+20E(IRI+20E).IRI was modeled by applying a tourniquet to the hind limb for 2 h with reperfusion for 1 h.5 mg/kg of 20E was administered intraperitoneally for 14 days.Afterward,the physical activity of mice,the histological structure of the quadriceps femoris,the expression of genes encoding proteins induced by hypoxia and involved in tissue adaptation to ischemia,and the functional parameters of skeletal muscle mitochondria were assessed.Results:It was shown that IRI of the limbs leads to functional disorders,depression of muscle function,accumulation of malondialdehyde(MDA)in mitochondria,and a decrease in their Ca2+buffering capacity,as well as an increase in the expression of HIF-1α,VGEF-A,PGC1αand PDGF-BB genes associated with adaptation to ischemia.20E reduced the intensity of degenerative processes in skeletal muscles,which was expressed in a decrease in the number of centrally nucleated fibers.Analysis of gene expression levels indicated a high degree of adaptation of animals to IRI.20E reduced the level of MDA in mitochondria,but did not affect the rate of respiration and calcium retention capacity of organelles both in normal conditions and during IRI.Conclusion:20E partially alleviates the skeletal muscle damage caused by IRI and can be used as part of combination therapy.
基金Supported by Zhejiang Provincial Natural Science Foundation of China,No.LQ23H020004The Medical and Health Research Project of Zhejiang province,No.2024KY983Basic Medical Health Technology Project of Wenzhou Science and Technology Bureau,No.Y20210818 and No.Y20210140.
文摘BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mechanism remains unclear.Circular RNAs(circRNAs),which are formed from protein-coding genes,can sequester microRNAs or proteins,modulate transcription and interfere with splicing.Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury.AIM To explore the role and mechanism of circRNAs in myocardial I/R injury.METHODS We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery,and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining.Then,left ventricular samples from different groups were selected for mRNA-sequence,and differential gene screening was performed on the obtained results.The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment analysis were performed,respectively.Then,the obtained circRNA and microRNA(miRNA)were paired for analysis,and the binding sites of miRNA and mRNA were virtual screened.Finally,the obtained circRNA,miRNA and mRNA were constructed by ceRNA mutual most useful network.RESULTS We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group.A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed(fold change≥2,P<0.05).GO and KEGG functional analyses of these circRNAs were performed.GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes.KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis.Furthermore,a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed,revealing that mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 might be key regulators of myocardial I/R injury.CONCLUSION This research provides new insights into the mechanism of myocardial I/R,which mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.
基金sponsored by Shandong Provincial Key Research and Development Program(Major Technological Innovation Project)([2021]CXGC010508)Guizhou Province Youth Science and Technology Talent Plan(YQK[2023]038)+1 种基金Science and Technology Department of Zunyi City of Guizhou province of China([2020]7)Key project at central government level:the ability establishment of sustainable use for valuable Chinese medicine resources(2060302).
文摘Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats were divided into the Control,Model,AMI positive control(Propranolol hydrochloride,30 mg/kg),low dose TFSB(50 mg/kg),and high dose TFSB(100 mg/kg)groups.Rats received the corresponding treatment by intragastric administration once daily for 10 consecutive days.Electrocardiogram,myocardial enzyme,triphenyltetrazolium chloride staining,hematoxylin-eosin,and enzyme-linked immunosorbent assay were performed to evaluate the protective effect of TFSB on AMI rats.Then,the UHPLC-Q-Orbitrap MS method based on serum metabolomics was utilised to search for metabolic biomarkers and metabolic pathways.Subsequently,Western blot and RT-PCR techniques were employed to identify the respective genes and proteins.Results:Pharmacodynamics revealed that TFSB could ameliorate AMI in rats.The results of the metabolomics analysis indicated that the alterations in metabolic profile observed in rats with AMI were partially improved by treatment with TFSB.Moreover,the mRNA expression levels of 5-lipoxygenase(5-LOX)and 15-lipoxygenase(15-LOX)and the protein expression levels of 5-LOX,15-LOX,interleukin-1β(IL-1β),and NF-κB p65 were reduced following treatment with TFSB.Conclusion:The potential treatment of TFSB in AMI may be ascribed to its ability to regulate arachidonic acid metabolism.
基金supported by the National Natural Science Foundation for Distinguished Young Scholars(No.81725021)the National Natural Science Foundation of China(Nos.82003633 and 82173705)。
文摘Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols(PPAPs),named hyperhomanoons A-E(1-5),and one known analog,hypersampsone O(6),were isolated from Hypericum patulum.Among these,compound 6 demonstrated potent protective effects against CoCl_(2)-induced hypoxic injury in hepatocytes.Furthermore,in a murine model of hepatic IRI induced by vascular occlusion,pretreatment with 6 markedly alleviated liver damage and reduced hepatocyte apoptosis.This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI,underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.
